KTX-582 is a potent IRAK4 degrader with DC50 values of 4 nM and 5 nM for IRAK4 and Ikaros, respectively. KTX-582 can induce apoptosis in MYD88MT DLBCL, and is efficient to induce in vivo tumor regressions in lymphoma model.
KTX-582 (compound I-41) degrades IRAK4 in whole blood monocyte and lymphocyte with IC50s of <0.05 μM[4].KTX-582 inhibits IRAK4 in human whole blood LPS TNFα with an IC50 of 0.05~1 μM[4].
References:
[1]. Matthew Weiss. Discovery and characterization of IRAKIMiDs: degraders targeting both IRAK4 and IMiD substrates for oncology indications. Northeastern Section, ACS (NESACS). [2]. Jennifer K. Lue, MD . Targeting MYD88-Mutant DLBCL with IRAKIMiDs: A Comparison to IRAK4 Kinase Inhibition and Evaluation of Synergy with Rational Combinations. American Society of Hematology ASH Annual Meeting [3]. Vogelmann A, Robaa D, Sippl W, Jung M. Proteolysis targeting chimeras (PROTACs) for epigenetics research. Curr Opin Chem Biol. 2020 Aug;57:8-16.
[4]. Nello Mainolfi, et al. Irak degraders and uses thereof. WO/2020/113233